Long Term Changes Of Postsynaptic Neuronal Excitability Of Activity-dependent

Dopamine is an important class of neurotransmitters in the central nervous system. It is involved in the regulation of spontaneous activity, mood, food intake, endocrine regulation, the regulation of sleep and other basic physiological functions as well as cognitive, learning and memory, drug addiction and other higher brain functions. Cell bodies synthesizing DA are mainly located in the ventral tegmental area (VTA). Hippocampus structure, the limbic system of the brain, performs the function of learning and memory, and spatial orientation, showing significant structural and functional plasticity. Recent studies have shown that hippocampal formation receives dopaminergic nerve input from cells located in the VTA and substantia nigra compacta. Ventral hippocampus has a density distribution of DA nerve terminals. Furthermore, the modulation of DA at hippocampus is closely related to cognition.At present, the activity-dependent synaptic plasticity is considered to be the molecular and cellular mechanisms of learning and memory, motivation, behavior and drug addiction process. The plasticity of intrinsic excitability change also is a possible mechanism of learning and memory because neural information is ultimately transmitted in form of patterns of action potential. So far, neuronal excitability plasticity has been paid more and more attention in recent years. There is evidence that excitability of DA neuron and the release amount of and DA neurotransmitter can be changed by addictive drugs such as amphetamine. They are not clear that relationship between the plasticity changes in the excitability of DA neurons and the neuronal activity level and relationship between the plasticity changes in the excitability of DA neurons and platicity of the neuron received synapse. Recent studies have confirmed that DA is not only involved in regulating plasticity of glutamatergic synapse in the hippocampus, but also involved in regulation of the intrinsic excitability of pyramidal neurons. Thus, the electrical activity of DA neurons can directly influence the normal function of hippocampal. However, there are few studies on changes of excitability after sustained excitatory activities in VTA DA neurons. Furthermore, it remains to be further studied whether DA and DA receptors are involved in the regulation of excitability changes of pyramidal neurons after sustained excitatory activities.To solve these problems, VTA DA neurons and hippocampal pyramidal neurons in slice were selected to be the subjects and patch-clamp was used in this study. Sustained excitatory activities of DA neuron and pyramidal neuron were triggered by high-frequency stimulation (HFS) on soma of DA neuron or Schaffer collateral. Aiming at obtaining the mechanism how intrinsic excitability change after sustained excitatory activities, it was observed that the excitability of the two kind of neurons after HFS on soma or HFS of presynaptic fibers with DA contributing to a better understanding of the neuronal working mechanisms in brain. This is the first observation HFS on soma and HFS of presynaptic fiber evoked long-term potentiation of intrinsic excitability (LTP-IE) of DA neuron or pyramidal neuron. Moreover, DA inhibited LTP-IE of hippocampal pyramidal neurons induced by presynaptic HFS through acting on Di receptor signal transduction pathway. The detail results are as follows:1. HFS on soma elicited DA neuron LTP-IEExcitability of dopaminergic neuron showed long-term potentiation by HFS on soma of DA neuron. Compared with initial state before HFS, the input resistance, rheobase and firing rate elicited by depolarizing current were decreased after HFS. Contemporarily, both steady-state whole-cell current and hyperpolarization-activated cation current were decreased too.2. Presynaptic HFS induced long-term potentiation of intrinsic excitability in hippocampal pyramidal neuronAn LTP-IE of pyramidal neuron was elicited with high frequency stimulation (HFS) at schaffer-collateral-CAl synapses. Compared with initial state, the input resistance and firing rate at100pA depolarizing current of pyramidal neuron were increased and rheobase was decreased after HFS. At the same time, the steady-state whole-cell current was reduced too.3. DA abolished HFS-induced LTP-IE of pyramidal neuron in hippocampal CA1areaDA was washed in2-3min before HFS, and washed out2-3min after the HFS. In the presence of dopamine, it was disappeared that the reduction of LTP-IE and steady-state whole-cell current. Compared with initial state, input resistance, rheobase, firing rate and steady-state whole-cell current of pyramidal neurons did not change after HFS.4. D1receptor but not D2receptor mediated the modulation of DAWe added the D1/D5receptor antagonist SCH23390to the perfusion solution1min before dopamine treatment;10μM SCH23390inverted the reduction of LTP of intrinsic excitability and steady-state whole-cell current. Compared with initial state, input resistance, rheobase, firing rate of pyramidal neuron increased after HFS. Meanwhile, steady-state whole-cell current decreased after HFS.When the SCH23390is changed to D2receptor antagonist sulpiride, DA decreased the LTP of intrinsic excitability and steady-state whole-cell current as before. Detail results were that input resistance, rheobase, firing rate and steady-state whole-cell current of pyramidal neurons did not change significantly after HFS, compared with initial state.Conclusion:Both HFS on soma and presynaptic HFS could induce LTP-IE of neuron. DA is involved in changes of excitability induced by sustained excitatory activities of pyramidal neurons in hippocampal CAl area. Moreover, the effect of DA is mediated by D1-like receptor signal transduction pathway and the details remains to be further studied.